Natural killer receptor-mediated regulation of dendritic cell functions in chronic hepatitis C

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Natural kilier (NK) cells are specialized lymphocytes that provide a first line of defense through their ability to kill pathogen-infected cells and transformed cells. The function of NK cells is regulated by a fine balance of inhibitory and activating signals, which are mediated by a diverse array of cell-surface receptors. We recently found that expression of the inhibitory receptor CD94/NKG2A is upregulated on NK cells in patients with chronic hapatitis C. HLA-E, a ligand for NKG2A, was expressed in all human hepatoma cell lines tested as well as non-transformed hepatocytes, but not in K562 cells, a classical NK-sensitive target. NK cells isolated from patients with chronic hepatitis C (HCV-NK) were less capable of killing hepatoma cells and of producing IFNγ in response to hepatoma cells than those from healthy donors, whereas there was no significant difference in NK responsiveness towards K562 cells. Of note is the finding that maturation and activation of monocyte-derived dendritic cells were negatively modulated in the presence of HCV-NK and hepatoma cells, which was restored by the addition of anti-NKG2A antibody during the coculture of HCV-NK and hepatoma cells. Research revealed that dendritic cells recognize danger signals from microorganisms by monitoring pathogen-associated molecular patterns via Toll-like receptors. Our findings have shed light on NK receptors as an important interface that transmits danger signals from abnormal cells to immune systems. Aberrant expression of CD94/NKG2A should have negative impact on innate resistance and subsequent adaptive immunity towards HCV-infected or transformed cells in chronic hepatitis C.